Diagnóstico das doenças pulmonares

Overview of pulmonary function testing in adults

NTRODUCTION — Evaluation of pulmonary function is important in many clinical situations, both when the patient has a history or symptoms suggestive of lung disease and when risk factors for lung disease are present, such as cigarette smoking [1]. An overview of pulmonary function testing will be presented here, summarizing the types of pulmonary function tests and their indications. Specific aspects of pulmonary function testing are discussed elsewhere. (See "Office spirometry" and "Reference values for pulmonary function testing" and "Diffusing capacity for carbon monoxide".)

PULMONARY FUNCTION TESTS — The major types of pulmonary function tests include spirometry, measurement of lung volumes, and quantitation of diffusing capacity. Measurements of maximal respiratory pressures and flow-volume loops, which record forced inspiratory and expiratory flow rates, are also useful in specific clinical circumstances (table 1).

Spirometry — Spirometry, which includes measurement of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), is the most readily available and most useful pulmonary function test. It takes 10 to 15 minutes, uses a $2000 instrument, and carries no risk. (See "Office spirometry" and "Flow-volume loops".)

The slow vital capacity (SVC) can also be measured with spirometers which collect data for at least 30 seconds. The SVC may be a useful measurement when the forced vital capacity (FVC) is reduced and airways obstruction is present. Slow exhalation results in a lesser degree of airway narrowing, and the patient may produce a larger, even normal vital capacity. In contrast, the vital capacity with restrictive disease is reduced during both slow and fast maneuvers. Thus, if the slow or forced vital capacity is within the normal range, it is generally unnecessary to measure static lung volumes (residual volume and total lung capacity) [2].

Flow-volume loop — Flow-volume loops, which include forced inspiratory and expiratory maneuvers, should be performed whenever stridor is heard over the neck during forced breathing or for evaluation of unexplained dyspnea. Airway obstruction located in the pharynx, larynx, or trachea (upper airways) is usually impossible to detect from standard FVC maneuvers. Reproducible forced inspiratory vital capacity (FIVC) maneuvers may detect variable upper airway obstruction [3], as can be seen with vocal cord paralysis or dysfunction, which causes a characteristic limitation of flow (plateau) during forced inhalation but little if any obstruction during exhalation (figure 1). (See "Flow-volume loops".)

Less commonly, a fixed upper airway obstruction (UAO) (eg, tracheal stenosis) causes flow limitation during both forced inhalation and forced exhalation maneuvers (figure 1). However, the flow-volume loop is not sensitive for detecting a fixed UAO, since the tracheal lumen is often reduced to less than 1 cm before a plateau is recognized. Poor effort mimics the flow-volume loop shapes of upper airway obstruction, but can be excluded when three or more maneuvers are seen to be reproducible.

Post-bronchodilator — Administration of albuterol by metered-dose inhaler (MDI) is indicated during an initial workup if baseline spirometry demonstrates airway obstruction or if one suspects asthma. Spirometry should be repeated ten minutes after administration of a bronchodilator; proper MDI technique is important to prevent false negative results. (See "The use of inhaler devices in adults".)

In a patient with airway obstruction, an increase in the FEV1 of more than 12 percent and greater than 0.2 L suggests acute bronchodilator responsiveness [4]. However, the lack of an acute bronchodilator response should not preclude a six to eight week therapeutic trial of bronchodilators and/or inhaled glucocorticoids, with reassessment of clinical status and change in FEV1 at the end of that time.

Lung volumes — Common lung volume measurements include total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) (figure 2). Measurement of the total lung capacity (TLC) may be helpful when the vital capacity is decreased. For example, in the setting of chronic obstructive pulmonary disease (COPD) with a low vital capacity, measurement of the TLC can help determine if there is a superimposed restrictive disorder.

There are four methods of measuring TLC:

Helium dilution
Nitrogen washout
Body plethysmography
Chest radiograph measurements
The first two methods are used extensively in hospital pulmonary function laboratories, but they may underestimate the TLC in patients with moderate to severe COPD. The gold standard for measurement of TLC, particularly in the setting of significant airflow obstruction, is body plethysmography.

Measurements of TLC using the chest radiograph or high resolution computed tomography (HRCT) correlate within 15 percent of those obtained by body plethysmography [5,6]. Since the TLC is equivalent to the amount of air seen in the lungs on a chest radiograph taken at maximal inspiration, it is important that the subject inhales maximally as the image is created.

Maximal respiratory pressures — Measurement of maximal inspiratory and expiratory pressures is indicated whenever there is an unexplained decrease in vital capacity or respiratory muscle weakness is suspected clinically. Maximal inspiratory pressure (MIP) is the maximal pressure that can be produced by the patient trying to inhale through a blocked mouthpiece. Maximal expiratory pressure (MEP) is the maximal pressure measured during forced expiration (with cheeks bulging) through a blocked mouthpiece after a full inhalation. Repeated measurements of MIP and MEP are useful in following the course of patients with neuromuscular disorders. The slow vital capacity may also be followed, but it is less specific and usually less sensitive.

Maximal inspiratory and expiratory pressures are easily measured using a simple mechanical pressure gauge connected to a mouthpiece. MIP measures the ability of the diaphragm and the other respiratory muscles to generate inspiratory force, reflected by a negative airway pressure. The average MIP and MEP for adult men are -100 and +170 cm H2O, respectively, while the corresponding values for adult women are about -70 and +110 cm H2O, respectively [7,8]. The lower limit of the normal range is about two-thirds of these values [4].

Diffusing capacity — Measurement of the single-breath diffusing capacity for carbon monoxide (DLCO, also known as transfer factor) is quick, safe, and useful in the evaluation of both restrictive and obstructive disease. It requires use of a piece of equipment that costs $20,000. In the setting of restrictive disease, the diffusing capacity helps distinguish between intrinsic lung disease, in which DLCO is usually reduced, from other causes of restriction, in which DLCO is usually normal. In the setting of obstructive disease, the DLCO helps distinguish between emphysema and other causes of chronic airway obstruction. (See "Diffusing capacity for carbon monoxide".)

Six-minute walk test — The six-minute walk test (6MWT) is a good index of physical function and therapeutic response in patients with chronic lung disease, such as COPD, pulmonary fibrosis, or pulmonary arterial hypertension [9-12]. The test should be performed according to standard methods [11]. During a 6MWT, healthy subjects can typically walk 400 to 700 m [9,13]. In addition to total distance walked, the magnitude of desaturation and timing of heart rate recovery have been associated with clinical outcomes. Studies to understand meaningful changes in six-minute walk distances have been conducted in several disease states. While there is some variability based on methods and study population, the available evidence suggests an improvement of about 30 m in distance walked is the minimally important difference (MID) [10,14-21]. While pulse oxygen saturation and heart rate are recorded before and after the test, the six-minute walk test is not designed to be an oxygen titration study, and a separate study should be performed to determine supplemental oxygen needs.

Oxygen desaturation during exercise — Assessment of oxygen saturation during exercise can be used to titrate the amount of oxygen needed to maintain adequate saturation during walking. A fall in SaO2 to 88 percent or less is an indication for supplemental oxygen, and confirmation with arterial blood gas (ABG) measurements may be indicated. (See "Pulse oximetry" and "Long-term supplemental oxygen therapy".)

Arterial blood gases — Arterial blood gases (ABGs) may be a helpful adjunct to pulmonary function testing in selected patients. The primary role of measuring ABGs in stable outpatients is to confirm hypoventilation when it is suspected on the basis of clinical history (eg, respiratory muscle weakness, advanced COPD), an elevated serum bicarbonate level, and/or chronic hypoxemia. ABGs also provide a more accurate assessment of the severity of hypoxemia in patients who have low normal oxyhemoglobin saturation [22].

INDICATIONS — Pulmonary function testing is useful for evaluation of a variety of forms of lung disease or for assessing the presence of disease in a patient with known risk factors, such as smoking. Other indications for pulmonary function tests include:

Evaluation of symptoms such as chronic persistent cough, wheezing, dyspnea, and exertional cough or chest pain
Objective assessment of bronchodilator therapy
Evaluation of effects of exposure to dusts or chemicals at work
Risk evaluation of patients prior to thoracic or upper abdominal surgery
Objective assessment of impairment or disability
Chronic dyspnea — Many lung diseases begin slowly and insidiously and finally manifest themselves with the nonspecific symptom of dyspnea on exertion. Pulmonary function tests are an essential part of the workup of such patients. In the outpatient setting, in which several days to weeks are available to make the diagnosis, a cost efficient method of ordering pulmonary function tests is to start with spirometry and then order further tests in a stepwise fashion to refine the diagnosis (algorithm 1). (See "Approach to the patient with dyspnea".)

When a patient is hospitalized and a diagnosis is needed within a day or two, a battery of pulmonary function tests may be ordered, often including spirometry before and after (pre- and post-) bronchodilator therapy, static lung volumes, and diffusing capacity. If the cause of dyspnea on exertion remains uncertain after these tests have been performed, cardiopulmonary exercise testing should be considered.

Asthma — Spirometry before and after a bronchodilator is indicated during the initial workup of patients suspected of having asthma (figure 3A-B). Spirometry is also indicated during most follow-up office visits to provide an objective measure of the therapeutic response [23]. (See "Diagnosis of asthma in adolescents and adults" and "Use of pulmonary function testing in the diagnosis of asthma".)

Cough or chest tightness with exercise or exposure to cold air, dusts, or fumes suggests bronchial hyperresponsiveness (BHR). However, BHR may not be detected by pre- and post-bronchodilator spirometry if the patient is asymptomatic at the time of evaluation. Commonly, the patient is asked to return for retesting when symptoms occur; however, this delays the diagnosis and may be impractical. Inhalation challenge testing can increase or decrease the pretest probability of asthma in less than an hour. (See "Bronchoprovocation testing".)

An alternative to inhalation challenge testing for the detection of airway hyperreactivity is measurement of airway lability for two weeks in the patient's own environment, using ambulatory monitoring of peak flow or FEV1. Children with asthma (not controlled by medication) typically demonstrate peak flow lability (amplitude/mean) in excess of 30 percent, while adults with active asthma have PEF lability greater than 20 percent. (See "Peak expiratory flow rate monitoring in asthma".)

A forced inspiratory maneuver performed as part of a flow-volume loop may be useful in detecting "vocal cord dysfunction" in atypical patients with a diagnosis of asthma who do not respond appropriately to therapy. (See "Evaluation of wheezing illnesses other than asthma in adults" and "Paradoxical vocal cord motion".)

Chronic obstructive pulmonary disease — Spirometry is the best method to detect or confirm airways obstruction in smokers with dyspnea (figure 3A) [24,25]. In these cases, the FEV1/FVC ratio and the FEV1 are decreased. Traditionally, values below 70 percent for the FEV1/FVC ratio and below 80 percent predicted for the FEV1 were used to define airflow obstruction. However, several studies suggest that use of fixed thresholds lead to misclassification, particularly in older adults [26,27]. Using the fifth percentile, the lower limit of normal (LLN), instead of the fixed value avoids misclassification of asymptomatic patients as having COPD. (See "Office spirometry", section on 'Ratio of FEV1/FVC'.)

Measurement of lung volumes by helium dilution and nitrogen washout may underestimate the total lung capacity (TLC) in patients with moderate to severe COPD. The gold standard for measurement of TLC, particularly in the setting of significant airflow obstruction, is body plethysmography. A concomitant restrictive ventilatory defect is detected in less than 10 percent of patients with a reduced FVC [28]. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging".)

Once the diagnosis of COPD is established, the course and response to therapy may be followed by observing changes in the FEV1, as was done in the multicenter Lung Health Study [29]. Continued smoking in a patient with airways obstruction often results in an abnormally rapid decline in FEV1 (90 to 150 mL/yr). On the other hand, smoking cessation often results in an increase in FEV1 during the first year, followed by a nearly normal rate of FEV1 decline (30 mL/yr). Both a low FEV1 and chronic mucus hypersecretion are predictors of hospitalization due to COPD [30].

Once the airways obstruction due to COPD has become very severe, with an FEV1 of 0.7 L or less, changes from visit to visit are usually within the error of the measurement (0.2 liters). In this circumstance, measurements of oxygen saturation during exercise and distance walked during six minutes may be more clinically meaningful for evaluating disease progression or therapeutic response than are changes in spirometry values [11,31].

Measurement of the diffusing capacity for carbon monoxide helps to distinguish between emphysema and other causes of chronic airway obstruction. As an example, emphysema lowers the DLCO, obstructive chronic bronchitis does not affect the DLCO, and asthma frequently increases the DLCO. (See "Diffusing capacity for carbon monoxide".) Changes in the DLCO in patients with established, smoking-related COPD are probably not clinically useful during follow-up visits, unless dyspnea suddenly worsens without an obvious cause.

Restrictive lung disease — The many disorders which cause reduction of lung volumes (restriction) may be divided into three groups:

Intrinsic lung diseases, which cause inflammation or scarring of the lung tissue (interstitial lung disease) or fill the airspaces with exudate or debris (acute pneumonitis)
Extrinsic disorders, such as disorders of the chest wall or the pleura, which mechanically compress the lungs or limit their expansion
Neuromuscular disorders, which decrease the ability of the respiratory muscles to inflate and deflate the lungs
The history, physical examination, and chest radiograph are often helpful in distinguishing among these disorders. Spirometry can be useful in detecting restriction (reduction) of lung volumes. If spirometry demonstrates reductions in FEV1 and/or FVC without evidence of airflow obstruction, evaluation of lung volumes and diffusing capacity are helpful in confirming the presence of restriction and assessing severity of impairment. Patients with mild interstitial lung disease may have normal values for FVC and TLC [32].

The DLCO is useful for differentiating intrinsic lung diseases, in which DLCO is generally reduced, from other causes of lung volume restriction, including neuromuscular disease or musculoskeletal deformity, in which DLCO is generally normal. (See "Diffusing capacity for carbon monoxide".)

Changes in the DLCO are also useful for following the course of or response to therapy in patients with interstitial lung disease. Pulse oximetry during a 6MWT is also useful in this setting, since oxygen saturation often falls during mild exercise in patients with interstitial lung disease and responds to successful therapeutic interventions [33]. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

Preoperative testing — Spirometry is useful for determining the risk of postoperative pulmonary complications in certain high-risk situations, including patients known to have COPD or asthma, current smokers, and those scheduled for thoracic or upper abdominal surgery [34]. The degree of airways obstruction (or an elevated PCO2 for patients with COPD) predicts the risk of postoperative pulmonary complications, such as atelectasis, pneumonia, and the need for prolonged mechanical ventilation. If spirometry demonstrates moderate to severe obstruction and the surgery can be delayed, a prophylactic program of pulmonary hygiene, including smoking cessation, inhaled bronchodilators or steroids, and antibiotics for bronchitis, will reduce the risk. However, the results of spirometry should not be used to deny surgery. Combining the results of spirometry with radioisotope or CT lung scans is also useful for predicting the remaining lung function following a lobectomy or pneumonectomy.

A number of studies indicate that the maximum oxygen uptake (as a percent of predicted), determined by cardiopulmonary exercise testing, is better than spirometry for predicting postsurgical complications [35], but the cost:benefit ratio is unknown. (See "Preoperative evaluation for lung resection".)

Impairment or disability — Most schemes for evaluation of respiratory impairment use pulmonary function tests, but the results in studies performed at rest are only a rough indication of an individual's ability to perform a given job. It is ideal to measure maximal oxygen consumption (VO2max), but this test is often not available to the primary care physicians who perform "disability" testing, or the expense is not reimbursed [36,37].

The American Medical Association provides guidelines for the classification of respiratory impairment based upon the results of spirometry or maximal oxygen consumption [38]. Of course, the results must be of good quality. Severe impairment (AMA class 4 with estimated 50 to 100 percent impairment) is defined as any one of the following:

Dyspnea after walking less than 100 meters on level ground
FVC less than 50 percent predicted
FEV1 less than 40 percent predicted
DLCO less than 40 percent predicted
VO2max less than 15 mL/kg per min
The Social Security Administration defines total respiratory disability using either height-corrected FEV1 (1.1 to 1.4 L) or a DLCO less than 30 percent predicted [39]. In one study, approximately 33 percent of patients who met the above criteria were dead after four years, compared with 7 percent of those who applied for disability but did not meet these criteria. (See "Evaluation of pulmonary disability".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Breathing tests (The Basics)")
SUMMARY AND RECOMMENDATIONS

Pulmonary function testing is indicated for evaluation of respiratory symptoms (eg, cough, wheezing, dyspnea, chest pain), bronchodilator therapy, effect of workplace exposure to dust or chemicals, and disability. It can also be used to assess severity and progression of lung diseases, such as asthma, chronic obstructive lung disease, and various restrictive diseases. (See 'Introduction' above.)
The major types of pulmonary function tests (PFTs) include spirometry, lung volumes, and diffusing capacity. Other PFTs include flow-volume loops (which record forced inspiratory and expiratory flow rates), measurements of maximal respiratory pressures, and the six-minute walk test. (See 'Pulmonary function tests' above.)
Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are the primary measurements obtained by spirometry. Their ratio (FEV1/FVC) is important for distinguishing obstructive airways disease and restrictive disease. A reduced ratio suggests obstructive airway disease and a normal ratio suggests restrictive disease, if accompanied by reduced lung volumes. (See 'Spirometry' above.)
Flow-volume loops can identify upper airway obstruction, which can be impossible to detect from standard FVC measurements. A characteristic limitation of flow (ie, a plateau) during forced inhalation suggests variable extrathoracic obstruction, while limitation of flow during forced exhalation suggests variable intrathoracic obstruction (figure 1). Fixed upper airway obstruction causes flow limitation during both forced inhalation and forced exhalation. (See "Flow-volume loops".)
Spirometry before and after the administration of a bronchodilator can be performed to detect bronchodilator responsiveness. An increase in the FEV1 of more than 12 percent and greater than 0.2 L suggests bronchodilator responsiveness; however, the lack of a bronchodilator response should not preclude a therapeutic trial of bronchodilators and/or inhaled glucocorticoids. (See 'Post-bronchodilator' above.)
Measurement of lung volumes complements spirometry. Common measurements include total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV). Decreased lung volumes suggest restrictive disease if accompanied by a normal FEV1/FVC ratio. Increased lung volumes suggest static hyperinflation due to obstructive airways disease if accompanied by decreased FEV1/FVC ratio. Coexisting restriction and obstruction can be detected, but requires both spirometry and lung volumes. (See 'Lung volumes' above.)
Measurement of diffusing capacity for carbon monoxide (DLCO) assesses gas exchange. Decreased DLCO accompanied by restrictive disease suggests intrinsic lung disease, whereas normal DLCO accompanied by restrictive disease suggests a non-pulmonary cause of restriction. Markedly decreased DLCO accompanied by obstructive airways disease suggests emphysema, whereas normal or mildly decreased DLCO suggests an alternative cause of obstructive airways disease. (See 'Diffusing capacity' above.)
Measurement of maximal inspiratory and expiratory pressures detects respiratory muscle weakness. Maximal inspiratory pressure (MIP) is the maximal pressure that can be produced by the patient trying to inhale through a blocked mouthpiece. Maximal expiratory pressure (MEP) is the maximal pressure measured during forced expiration through a blocked mouthpiece after a full inhalation. (See 'Maximal respiratory pressures' above.)
Pulse oximetry is used to screen for oxygen desaturation in patients with exercise limitation and to determine the adequacy of supplemental oxygen therapy. A fall of more than 4 percent (ending at a saturation below 93 percent) suggests significant desaturation, which can be confirmed with arterial blood gas measurements.


Approach to the adult with interstitial lung disease: Diagnostic testing

INTRODUCTION — The diffuse parenchymal lung diseases, often collectively referred to as the interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations (algorithm 1) [1-4]. The descriptive term "interstitial" reflects the pathologic appearance that the abnormality begins in the interstitium, but the term is somewhat misleading, as most of these disorders are also associated with extensive alteration of alveolar and airway architecture.

The initial evaluation of patients with ILD is aimed at identifying the etiology of the ILD and its severity. The results of laboratory, radiographic, and pulmonary function tests guide the decisions about whether to pursue bronchoalveolar lavage and/or transbronchoscopic, thoracoscopic, or open lung biopsy.

An overview of the diagnostic testing that is helpful in the diagnosis of ILD will be presented here (algorithm 2) [5-7]. The clinical findings that aid in the diagnosis of ILD and the individual causes of ILD are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Idiopathic interstitial pneumonias: Clinical manifestations and pathology" and "Clinical manifestations and diagnosis of sarcoidosis" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of diffuse parenchymal lung disease (ILD) includes those ILDs that are associated with a broad range of diseases (table 1), exposures (table 2A-B), and drugs (table 3). ILD may also occur as an idiopathic condition (algorithm 1). The treatment choices and prognosis vary among the different causes and types of ILD, so ascertaining the correct diagnosis is important.

A variety of infectious processes cause interstitial opacities on chest radiograph, including fungal pneumonias (eg, coccidioidomycosis, cryptococcosis, Pneumocystis jirovecii), atypical bacterial pneumonias, and viral pneumonias. These infections often occur in immunocompromised hosts and are discussed separately. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

The most common identifiable causes of ILD are exposure to occupational and environmental agents (table 2A-B), especially to inorganic or organic dusts, and drug-induced pulmonary toxicity (table 3). (See "Asbestosis" and "Chronic beryllium disease (berylliosis)" and "Silicosis" and "Classification and clinical manifestations of hypersensitivity pneumonitis (extrinsic allergic alveolitis)" and "Diagnosis of hypersensitivity pneumonitis (extrinsic allergic alveolitis)".)

ILD can potentially complicate the course of most of the connective tissue diseases (eg, polymyositis/dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease).

Idiopathic causes of ILD include sarcoidosis, cryptogenic organizing pneumonia, and the idiopathic interstitial pneumonias (algorithm 1). The idiopathic interstitial pneumonias have been further characterized: idiopathic pulmonary fibrosis (usual interstitial pneumonia), desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, acute interstitial pneumonia, and nonspecific interstitial pneumonia. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology".)

LABORATORY TESTS — The routine laboratory evaluation typically includes biochemical tests to evaluate hepatic and renal function; hematologic tests with differential blood count to check for evidence of anemia, polycythemia, leukocytosis, or eosinophilia; urinalysis; and creatine kinase for myositis (table 4) [1]. Depending on the clinical situation and results of hepatic function tests, hepatitis serology and HIV testing may be appropriate.

Serologic studies are obtained to ensure that hypersensitivity pneumonitis and subclinical connective tissue disease are not overlooked. However, not all patients with positive serologic tests will develop a well-differentiated connective tissue disease. We typically obtain a hypersensitivity precipitin panel, anti-nuclear antibodies (ANA), rheumatoid factor, anti-topoisomerase (anti-Scl70), and anti-neutrophil cytoplasmic antibodies (ANCA) [2]. We also obtain anti-JO-1 antibodies even in the absence of clinical myositis, as ILD precedes the onset of myositis in about 70 percent of patients with the anti-synthetase syndrome [3]. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis".)

For patients with a positive ANA, we usually obtain anti-double-stranded DNA and anti-extractable nuclear antigen antibodies (anti-Sm, anti-ribonucleoprotein) to further evaluate for systemic lupus erythematosus and mixed connective tissue disease. (See "Measurement and clinical significance of antinuclear antibodies" and "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)

For patients presenting with pulmonary hemorrhage, we typically test for antiglomerular basement membrane antibodies, ANCA, ANA, antiphospholipid antibodies, and antistreptococcal antibodies. (See "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.)

We generally do not find it helpful diagnostically to obtain a C-reactive protein level or a sedimentation rate, as these are entirely nonspecific. Hypergammaglobulinemia is commonly observed in patients with ILD, but is also nondiagnostic. (See "Acute phase reactants".)

Serum angiotensin converting enzyme (ACE) levels are generally not helpful in the initial evaluation of ILD, because of the low sensitivity and specificity of the test. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Serum ACE'.)

A number of serum markers suggestive of ILD have been identified, including surfactant protein A and B (SP-A, SP-B), monocyte chemoattractant protein-1 (MCP-1), and Kerbs von Lungren (KL)-6, a circulating, high-molecular weight glycoprotein expressed by type II pneumocytes [4-6,8,9]. In one report, the receiver operating characteristics of these four markers were evaluated in a mixed population of patients with idiopathic ILD, collagen vascular disease-associated ILD, and controls with and without pulmonary disease [5]. KL-6 was associated with the highest sensitivity, specificity and diagnostic accuracy for the presence of ILD (94, 96, and 94 percent, respectively). The clinical role of these serum markers in the diagnosis of ILD is unclear and these tests are generally not commercially available.

In the future, the KL-6 assay may help to identify and monitor interstitial lung disease in patients with rheumatoid arthritis and other connective tissue diseases. (See "Interstitial lung disease in rheumatoid arthritis".)

IMAGING

Chest radiography — The most common radiographic abnormality on routine chest radiograph is a reticular pattern (image 1); however, nodular (image 2) or mixed patterns (alveolar filling and increased interstitial markings) are not unusual (table 5A-C) [7]. Although the chest radiograph is useful in suggesting the presence of ILD, the correlation between the radiographic pattern and the stage of disease (clinical or histopathologic) is generally poor. Only the radiographic finding of honeycombing (small cystic spaces) correlates with pathologic findings and, when present, portends a poor prognosis.

In the evaluation of ILD, it is important to review all previous chest films to assess the rate of change in disease activity.

The chest radiograph is normal in as many as 10 percent of patients with some forms of ILD, particularly those with hypersensitivity pneumonitis. Thus, a complete evaluation should be undertaken even if a symptomatic patient has a normal chest radiograph or an asymptomatic patient has radiographic evidence of ILD. Failure to adequately evaluate such individuals may lead to disease progression that is irreversible by the time the patient seeks additional medical attention. The radiologic patterns and disease distributions associated with specific ILDs are discussed separately. (See "Evaluation of diffuse lung disease by conventional chest radiography".)

Computed tomography — High resolution computed tomography (HRCT) is obtained in almost all patients with diffuse pulmonary parenchymal disease. We typically obtain both supine and prone images to avoid confusing dependent atelectasis with interstitial opacities. Comparing inspiratory and expiratory views is helpful when bronchiolitis is suspected. (See "High resolution computed tomography of the lungs" and "Bronchiolitis in adults", section on 'Chest imaging'.)

HRCT provides greater diagnostic accuracy than the plain chest radiograph, but several series have reported inconsistency among observers in the accuracy of differentiating between the ILDs [10-12]. In addition, it is difficult to extrapolate from the diagnostic accuracy in carefully controlled series to that in routine clinical practice because of variability in radiologic experience and scanning protocols.

However, certain HRCT findings help to narrow the differential diagnosis of ILD. The correlations between the various HRCT patterns and likely diagnoses are shown in the table (table 6A-B) [7,13-16]. (See "High resolution computed tomography of the lungs".) As examples:

Bilateral symmetric hilar adenopathy and upper lung zone reticular opacities suggest sarcoidosis or another granulomatous disease
Pleural plaques with linear calcification suggest asbestosis
Centrilobular nodules that spare the subpleural region are seen in hypersensitivity pneumonitis, sarcoidosis, Langerhans cell histiocytosis and also respiratory, follicular, and cellular bronchiolitis
Irregular cysts associated with nodules in the upper and middle lung zones suggest pulmonary Langerhans cell histiocytosis
Subpleural and bibasilar reticular opacities associated with honeycomb changes and traction bronchiectasis are suggestive of idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, or ILD-associated with rheumatoid arthritis
In an asymptomatic patient, diffuse, calcified, nodular, interstitial opacities may reflect healed varicella-zoster pneumonia [17]
Gallium-67 lung scanning — Gallium-67 lung scanning is of limited value as a means of evaluating patients with ILD. We do not obtain gallium-67 lung scans in the evaluation of patients with ILD.

FDG-PET scanning — The role of (18)F-2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) scanning in the evaluation of ILD is unclear. In a series of 35 patients with pulmonary lymphangitic carcinomatosis, diffuse uptake of FDG was noted in 30 patients and focal uptake in four [18]. However, positive FDG uptake can also be seen in sarcoidosis and pulmonary Langerhans cell histiocytosis. We do not typically obtain PET scans in the evaluation of ILD. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'PET scan' and "Pulmonary Langerhans cell histiocytosis", section on 'Fluorodeoxyglucose-PET scan'.)

CARDIAC EVALUATION — An electrocardiogram is typically obtained to evaluate for evidence of pulmonary hypertension or concurrent cardiac disease. If heart failure is suspected, a serum brain natriuretic peptide level is measured. (See "Approach to the patient with dyspnea", section on 'Heart failure' and "Approach to the patient with dyspnea", section on 'Plasma BNP'.)

There are no clear guidelines on when to obtain a transthoracic echocardiogram in a patient with ILD. A reasonable approach is to perform echocardiography in patients with an abnormal electrocardiogram, suspected heart failure, rapid onset of radiographic findings, or a moderate to severe reduction in diffusing capacity (DLCO); this later feature may suggest concomitant pulmonary hypertension. If it has not been performed previously, echocardiography is typically performed before obtaining a surgical lung biopsy to exclude occult heart failure. (See 'Diffusing capacity' below and "Noninvasive methods for measurement of left ventricular systolic function", section on 'Echocardiography' and "Clinical features and diagnosis of pulmonary hypertension in adults", section on 'Echocardiography'.)

Assessment for concomitant pulmonary hypertension is important because the presence of pulmonary hypertension may be a clue to the underlying ILD etiology (eg, systemic sclerosis, mixed connective tissue disease) or severity. In addition, among patients with idiopathic pulmonary fibrosis (IPF), pulmonary hypertension is associated with increased disease severity and decreased survival. (See "Pulmonary hypertension associated with interstitial lung disease", section on 'Prognosis'.)

PULMONARY FUNCTION TESTING — Complete lung function testing (spirometry, lung volumes, diffusing capacity) and resting and exercise pulse oximetry are obtained in virtually all patients with suspected ILD [1,19,20]. Measurement of lung function is most helpful for assessing the severity of lung involvement in patients with ILD. In addition, the finding of an obstructive, restrictive, or mixed pattern is useful in narrowing the number of possible diagnoses.

Arterial blood gases are often obtained to corroborate results of pulse oximetry. (See "Overview of pulmonary function testing in adults" and "Office spirometry".)

Spirometry and lung volumes — Most of the interstitial disorders have a restrictive defect with reductions in total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) [21,22]. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) are decreased, but usually the changes are in proportion to the decreased lung volumes; thus, the FEV1/FVC ratio is usually normal or increased (figure 1). The reductions in lung volumes become more pronounced as lung stiffness increases with disease progression (figure 2). (See "Overview of pulmonary function testing in adults", section on 'Restrictive lung disease'.)

In contrast, an interstitial pattern on chest radiograph accompanied by obstructive airflow limitation (ie, a reduced FEV1/FVC ratio) on lung function testing is suggestive of any of the following processes:

Sarcoidosis
Lymphangioleiomyomatosis
Hypersensitivity pneumonitis
Pulmonary Langerhans cell histiocytosis
Tuberous sclerosis and pulmonary lymphangioleiomyomatosis
Combined COPD and ILD
Constrictive bronchiolitis
Diffusing capacity — A reduction in the diffusing capacity (DLCO) is a common, but nonspecific finding in ILD. The decrease in DLCO is due, in part, to effacement of the alveolar capillary units but more importantly, to the extent of mismatching of ventilation and perfusion of the alveoli. In some ILDs, particularly sarcoidosis, there can be considerable reduction in lung volumes and/or severe hypoxemia but normal or only slightly reduced DLCO. (See "Diffusing capacity for carbon monoxide".)

Moderate to severe reduction of DLCO in the presence of normal lung volumes in a patient with ILD suggests one of the following:

Combined emphysema and ILD
Combined ILD and pulmonary vascular disease
Pulmonary Langerhans cell histiocytosis
Pulmonary lymphangioleiomyomatosis
Pulmonary vascular disease, and thus a reduction in DLCO, can develop in patients with ILD as a consequence of hypoxemic vasoconstriction, thromboembolic disease complicating the ILD, or a disease with both ILD and pulmonary hypertension, such as scleroderma.

In general, the severity of the DLCO reduction does not correlate well with disease prognosis, unless the DLCO is less than 35 percent of predicted [23]. Longitudinal changes in DLCO have been used to assess disease progression or regression. Due to difficulties with reproducibility in measuring DLCO, a change of 15 percent is needed to identify a true change in disease severity [1].

Gas exchange at rest and on exertion — Resting arterial blood gases may be normal in early ILD or may reveal hypoxemia (secondary to mismatching of ventilation to perfusion) and respiratory alkalosis. Carbon dioxide retention is rare and usually a manifestation of end-stage disease. (See "Arterial blood gases".)

Normal values for resting arterial partial pressure of oxygen (PaO2) or pulse O2 saturation do not rule out significant hypoxemia during exercise or sleep. Thus, it is important to perform exercise testing with serial measurement of arterial blood gases or pulse oximetry (figure 3). Exercise testing may take the form of a cardiopulmonary exercise test, a six-minute walk test, or informal ambulatory oximetry including a stair climb to replicate the patient's usual daily activity. (See "Overview of pulmonary function testing in adults", section on 'Oxygen desaturation during exercise'.)

In a cardiopulmonary exercise test, arterial oxygen desaturation, a failure to decrease dead space appropriately with exercise (ie, a high VD/VT ratio), and an excessive increase in respiratory rate with a lower than expected recruitment of tidal volume provide useful information regarding physiologic abnormalities and the extent of disease. Full cardiopulmonary exercise testing is not necessary for every patient with ILD. However, when the significance of symptoms or radiographic abnormalities is unclear, a normal maximal cardiopulmonary exercise test effectively excludes significant ILD [1]. (See "Exercise physiology" and "Oxygenation and mechanisms of hypoxemia".)

Serial assessment of resting and exercise gas exchange is one of the methods used to follow ILD activity and responsiveness to treatment, especially in idiopathic pulmonary fibrosis (IPF). As an example, the results of six-minute walk testing (6MWT) have correlated with prognosis in several studies of IPF [24-27]. Pulse oximetry desaturation to 88 percent or below during the 6MWT is associated with a median survival of 3.21 years compared with a median survival of 6.63 years in those who did not desaturate below 89 percent [25]. The distance walked during the 6MWT is a reproducible measure and correlates with the maximal oxygen consumption (VO2max) obtained during a maximal exercise test [27].

ROLE OF BRONCHOALVEOLAR LAVAGE — Bronchoalveolar lavage (BAL) is performed during flexible bronchoscopy to obtain samples of cells and fluid from the distal airways and alveoli [28]. The lavage fluid is sent for cell counts, cultures for mycobacterial, viral and fungal pathogens, and cytologic analysis (table 7 and table 8 and table 9 and table 10). (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Virtually all patients presenting with hemoptysis and radiographic ILD should undergo BAL promptly to confirm an alveolar source of bleeding and identify any infectious etiologies. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Hemorrhagic BAL' and "The diffuse alveolar hemorrhage syndromes".)

The majority of patients with an acute onset of ILD will undergo BAL to evaluate for acute eosinophilic pneumonia, alveolar hemorrhage, malignancy, and opportunistic or atypical infection, which can often be diagnosed on the basis of BAL findings (table 7). (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Eosinophilic BAL' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Hemorrhagic BAL' and "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Invasive procedures'.)

For patients with a subacute or chronic presentation of ILD, BAL is often performed when sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans histiocytosis, or infection are suspected based on the radiographic pattern (eg, upper lobe predominance of reticular opacities, hilar lymphadenopathy, irregular cystic airspaces), history of exposure (eg, bird keeping, farming), or concomitant clinical findings (eg, hemoptysis, renal insufficiency). In these patients, the results of BAL analysis may be used to narrow the differential diagnostic possibilities between various types of ILD, but tissue confirmation is usually required (table 11 and table 10). (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Bronchoalveolar lavage' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL' and "Pulmonary Langerhans cell histiocytosis", section on 'Bronchoalveolar lavage'.)

BAL is less likely to be helpful in patients with a radiographic pattern suggestive of idiopathic pulmonary fibrosis [29,30]. BAL does not have an established role in the assessment of ILD progression or response to therapy.

ROLE OF LUNG BIOPSY — When the results of the above evaluation do not allow the clinician to make a confident diagnosis of a given type or stage of ILD, lung biopsy with careful examination of lung tissue may be necessary [1,31]. This decision must be made on a case-by-case basis, weighing the morbidity of the procedure, the likely diagnoses, the toxicity of therapy, and the values and preferences of the patient. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Indications'.)

We typically obtain a lung biopsy in patients with atypical or progressive symptoms and signs (age less than 50 years, fever, weight loss, hemoptysis, signs of vasculitis), atypical radiographic features, unexplained extrapulmonary manifestations, rapid clinical deterioration, or sudden change in radiographic appearance.

Occasionally, the noninvasive evaluation will yield conflicting findings, which may require a lung biopsy for clarification. As an example, a cardiopulmonary exercise test may indicate that ILD is the most likely cause of a patient's symptoms and signs, while their high resolution computed tomography (HRCT) shows only minimal interstitial changes. In this situation, a lung biopsy may be indicated to confirm that an ILD, rather than another process, is the cause of the patient's clinical findings, thus enabling appropriate treatment.

Lung biopsy may also be indicated to exclude neoplastic and infectious processes. As an example, sarcoidosis can sometimes have a similar HRCT appearance to lymphangitic carcinomatosis or hypersensitivity pneumonitis (table 6A-B). Or, a patient with rheumatoid arthritis might develop ILD due to the underlying disease, drugs used in treatment, or tuberculosis.

Patients with minimal symptoms, signs, physiologic impairment, and radiographic abnormalities may prefer close observation over several months with interval repetition of pulmonary function tests and HRCT, rather than proceeding immediately to lung biopsy. Other patients prefer to undergo a lung biopsy sooner to obtain a definitive diagnosis, rather than watchful waiting.

Lung biopsy may be obtained by flexible bronchoscopy, video-assisted thoracoscopic (VATS) biopsy, or open lung biopsy. These techniques and the reasons to choose one over another are discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Specimen collection'.)

The histopathologic pattern found on the lung biopsy specimen is evaluated in combination with the clinical information to determine the diagnosis. The histopathologic patterns of common interstitial lung diseases are described separately. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology" and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Interpretation of histopathologic patterns'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Idiopathic pulmonary fibrosis (The Basics)" and "Patient information: Interstitial lung disease (The Basics)")
SUMMARY AND RECOMMENDATIONS

Diffuse parenchymal lung diseases, often collectively referred to as interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations (algorithm 1). (See 'Introduction' above.)
The differential diagnosis of diffuse parenchymal lung diseases includes a broad range of diseases, from those that are associated with a long list of known causes (table 2A-B) and associations (table 1) to those that are idiopathic (algorithm 1). (See 'Differential diagnosis' above.)
The treatment choices and prognosis vary among the different causes and types of ILD, so ascertaining the correct diagnosis is important. An algorithm for evaluating a patient with ILD is provided in the figure (algorithm 2). (See 'Differential diagnosis' above.)
The routine laboratory evaluation is often nonspecific, but should include biochemical tests to evaluate hepatic and renal function; hematologic tests with differential blood count to check for evidence of anemia, polycythemia, leukocytosis, or eosinophilia; urinalysis; and creatine kinase for myositis (table 4). Additional serologic testing is often obtained, based on the results of the clinical findings. (See 'Laboratory tests' above.)
High resolution computed tomography (HRCT) is obtained in almost all patients with diffuse pulmonary parenchymal disease. We typically obtain both supine and prone images to avoid confusing dependent atelectasis with interstitial opacities. Expiratory views are helpful when a condition associated with air-trapping (ie, bronchiolitis) is suspected. (See 'Imaging' above and "High resolution computed tomography of the lungs".)
Certain HRCT findings help to narrow the differential diagnosis of ILD. The correlations between the various HRCT patterns and likely diagnoses are shown in the table (table 6A-B). (See 'Imaging' above and "High resolution computed tomography of the lungs".)
An electrocardiogram is typically obtained to evaluate for evidence of pulmonary hypertension or concurrent cardiac disease. If heart failure is suspected, a serum brain natriuretic peptide level is measured. An echocardiogram is also obtained when there is suspicion for heart failure or pulmonary hypertension. (See 'Cardiac evaluation' above.)
Complete lung function testing (spirometry, lung volumes, diffusing capacity) and exercise pulse oximetry are obtained in all patients with suspected ILD. Resting room air arterial blood gases are often obtained to corroborate findings of pulse oximetry. (See 'Pulmonary function testing' above.)
In virtually everyone presenting with hemoptysis and radiographic ILD, BAL is performed promptly to confirm an alveolar source of bleeding and identify infectious etiologies, if present. The majority of patients with an acute onset of ILD will also undergo bronchoalveolar lavage (BAL) to evaluate for alveolar hemorrhage, malignancy, and opportunistic or atypical infection. (See 'Role of bronchoalveolar lavage' above and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
In patients with a more chronic presentation, the BAL is less helpful, as the findings are typically nonspecific. However, when sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans histiocytosis, or infection are suspected based on the radiographic pattern, history of exposure, or concomitant clinical findings, BAL may help to narrow the differential diagnosis. (See 'Role of bronchoalveolar lavage' above and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
When it is not possible to make a confident diagnosis or to stage the disease after an initial noninvasive evaluation, lung biopsy with careful examination of lung tissue may be necessary. This decision is made on a case-by-case basis, weighing the morbidity of the procedure, the likely diagnoses, the toxicity of therapy, and the values and preferences of the patient.


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